Each year 400,000 children are born with port wine stain (PWS) birthmarks. They and their families are confronted with the devastating psychological and physical consequences of this disease. This proposal is a multidisciplinary collaboration between basic and physician scientists designed to improve treatment of pediatric PWS and provide clinical translation of a novel therapeutic regimen, combined photodynamic therapy (PDT) and pulsed dye laser (PDL) treatment (hereafter termed PDT+PDL). Our preliminary data indicate that the combined protocol can enhance the removal of targeted microvasculature. Our long-term goal is to eliminate the physical and psychosocial trauma associated with these lesions. The objective of this application is to investigate the safety and efficacy of PDT+PDL. The central hypothesis is that PDT+PDL will achieve enhanced PWS skin blanching, compared to conventional PDL alone. Our specific aims are to: 1) Identify PDT+PDL therapeutic protocols with clinical applicability; 2) Identify candidate mechanisms of action of the PDT+PDL protocol; 3) Identify clinically relevant light doses with therapeutic efficacy and 4) Determine clinical outcomes of the selected PDT+PDL protocol on adolescent and adult patients. The proposed translational research is innovative because it will introduce a novel treatment method to the field of pediatric dermatological therapy. The expected outcome is a paradigm shift in the clinical management of PWS birthmarks in order to dramatically improve treatment results. Successfully removing PWS birthmarks in children will eliminate the psychosocial damage these lesions inflict, and will significantly and positively impact the life of affected individuals and their families. Such an outcome will contribute to the NIH mission of methodology development to improve fundamentally the treatment of disease.